SPID#: 4 The aim of this project is to investigate in a nonhuman primate model the biochemical mechanisms that mediate the behavioral and respiratory effects of caffeine and related xanthines. Research efforts during 1995 continued to develop a model of caffeine tolerance. Results demonstrated that tolerance to the respiratory effects of caffeine was rapid, surmountable and fully reversible. The effects of rolipram and Ro 20-1724, selective PDE inhibitors, were less pronounced during chronic administration of caffeine, demonstrating cross-tolerance. Tolerance to the respiratory-stimulant effects of caffeine was less evident during conditions of normocapnia compared to hypercapnia. The latter results may have important implications regarding the neural control of respiration and the biochemical mechanisms of action of xanthines. Related studies demonstrated tolerance to the effects of caffeine on operant behavior with a dosing regimen similar to that used in respiratory studies. Additionally, cross-tolerance was demonstrated to the xanthine, theophylline, but not to the non-xanthine stimulant, cocaine. A second study demonstrated that caffeine and nicotine stimulate respiration through different pharmacological mechanisms, in contrast to caffeine and its metabolites which exhibited a similar pharmacological profile. Moreover, significant pharmacokinetic interactions were obtained when caffeine and nicotine were co- administered. Altered sensitivity to drugs with selective mechanisms of action will provide a basis for comparing biochemical and cellular mechanisms that mediate the effects of xanthines on behavior and respiration.